Plasmatherapy in Atypical Hemolytic Uremic Syndrome Chantal Loirat, M.D.,1 Arnaud Garnier, M.D.,1 Anne-Laure Sellier-Leclerc, M.D.,1 and Theresa Kwon, M.D.1

ABSTRACT

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Plasmatherapy has become empirically first-line treatment in atypical hemolytic uremic syndrome (aHUS), although no prospective controlled trials have been conducted. Patients with mutations that induce complete or partial factor H (FH) quantitative deficiency may be controlled by plasma infusions (PI), but plasma exchanges appear more efficient than PI in patients with mutations that result in a mutant dysfunctional FH in the circulation. Early treatment is crucial. Long-term prophylactic plasmatherapy appears more efficient to prevent end-stage renal disease (ESRD) than plasmatherapy only during relapses. However, the longest follow-up with preserved renal function under plasmatherapy is only 6.5 years. Plasmatherapy does not appear to influence the outcome of aHUS with membrane cofactor protein mutation, and its efficacy in patients with factor I, C3, or factor B mutations is suggested by a few reports. We hope complement blockers will offer patients a better chance to avoid ESRD and provide a better quality of life. KEYWORDS: Atypical hemolytic uremic syndrome, plasma infusions, plasma exchange, complement

O

ver the last decade, atypical hemolytic uremic syndrome (aHUS) has been demonstrated to be a disorder of the complement alternative pathway regulation.1 Four alternative pathway regulatory proteins—factor H (FH), membrane cofactor protein (MCP or CD46), factor I (FI), and thrombomodulin (THBD)—and two proteins of the C3 convertase—factor B (FB) and C3— are now implicated. The overall mortality in the acute phase is
10%, and evolution to end-stage renal disease (ESRD) occurs in 50% of patients.1–4 Plasmatherapy was first considered for HUS patients 30 years ago when its benefit was demonstrated in thrombotic thrombocytopenic purpura (TTP).5–8 However, until the 1990s, the distinction between HUS due to Shiga-toxin-producing Escherichia coli (STEC-HUS)

and aHUS, or between aHUS due to complement dysregulation and TTP due to hereditary or immune ADAMTS-13 deficiency was not established. Therefore, the only two prospective randomized trials ever performed in HUS, nearly 25 years ago, which showed no clear benefit from plasma infusions (PI) in children with HUS.9,10 cannot be regarded as arguments against plasmatherapy in aHUS because they did not differentiate patients with STEC-HUS (probably the majority, now known as nonresponsive to plasmatherapy) from those with aHUS or TTP.11,12 When these differentiations were clarified, plasmatherapy empirically became first-line treatment in aHUS.13,14 Here we review the published data and recommendations for plasmatherapy in aHUS according to

1 Assistance Publique-Hoˆpitaux de Paris, Pediatric Nephrology Department, Universite´ Paris-Diderot, Hoˆpital Robert Debre´, Paris, France. Address for correspondence and reprint requests: Chantal Loirat, M.D., Pediatric Nephrology Department, Hoˆpital Robert Debre´, 48 Boulevard Serurier, 75019 Paris, France (e-mail: chantal.loirat@ rdb.aphp.fr).

Hemolytic Uremic Syndrome; Guest Editors, Reinhard Wu¨rzner, M.D., Ph.D., and Lothar-Bernd Zimmerhackl, M.D., Ph.D. Semin Thromb Hemost 2010;36:673–681. Copyright # 2010 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI: http://dx.doi.org/10.1055/s-0030-1262890. ISSN 0094-6176.

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genotype. Plasmatherapy in anti-FH antibodies aHUS and post-transplant aHUS recurrence is developed in other articles of this issue of Seminars in Thrombosis and Hemostasis.

THE RATIONALE OF PLASMATHERAPY IN ATYPICAL HEMOLYTIC UREMIC SYNDROME Plasmatherapy consists of either infusion of freshfrozen plasma (FFP) or plasma exchange (PE) with volume restitution by FFP. Viro-inactivated/pathogenreduced FFP produces normal amounts of complement factors FH, FI, FB, and C3. FFP does not contain MCP and THBD, two noncirculating transmembrane proteins. First, PE allows delivery of high quantities of FFP (generally 40 to 60 mL/kg per session), and thus of nonmutated factors, without the risk of volume overload, hypertension and cardiac failure, and hyperproteinemia, a complication with possible deleterious hemorheologic and renal consequences, when PI (10 to 20 mL/kg per infusion) are repeated two to three times weekly.15,16 Second, it also allows removal of mutated factors. Theoretically, this may be important when the mutation results in a dysfunctional protein. Most mutations of CFH and all those in CFI, CFB, and C3 reported in aHUS are heterozygous, suggesting a dominant negative effect of the mutant protein on the normal protein. Third, PE could also be of benefit by removing other triggers (e.g., cytokines) of endothelial dysfunction and platelet hyperaggregability. The analysis of the effect of plasmatherapy in retrospective case series is difficult because of varying parameters (e.g., delay between onset of HUS and initiation of treatment; plasmatherapy modalities [PI or PE; if PE, restitution with either albumin or FFP]; volume of FFP infused or exchanged; frequency and duration are not homogeneous). No prospective randomized controlled trials to prove the efficacy of plasmatherapy have been conducted in aHUS. Therefore, although most patients received some form of plasmatherapy, only a limited number of case reports are available to answer the question of the benefit of plasmatherapy in aHUS. Plasma sensitivity is generally defined by the increase of platelet count and cessation of hemolysis (stabilized hemoglobin, normalization of lactate dehydrogenase [LDH] ,and haptoglobin levels). Plasmatherapy may fail to rescue renal function despite hematologic remission if treatment initiation has been delayed and/or histological lesions are irreversible. Therefore, the response to plasmatherapy may be complete (hematologic and renal remission) or partial (hematologic remission with renal sequelae).

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PLASMATHERAPY IN PATIENTS WITH CFH MUTATIONS Prognosis of aHUS associated with CFH mutations is the most severe, with evolution to death (20 to 30% of patients) or ESRD (40% of survivors) at first episode or during the year of onset in 60 to 70% of patients.1–4

Retrospective Series The main retrospective series was published in 2006 by Caprioli et al.2 Most aHUS episodes (57 of 61 episodes in 47 patients) were treated by plasmatherapy, consisting of PI 10 to 20 mL/kg and/or PE 30 to 40 mL/kg, for a total of 2 to 36 treatments in 2 to 6 weeks. A complete or partial remission was observed in 38 of 57 treated episodes (67%) and 4 of 4 untreated. However, 30% of patients died, 22% went on to ESRD, 30% had renal sequelae, and only 17.5% had complete remission at first episode; 78% had died or developed ESRD at long-term follow-up.

Case Reports CFH mutations are classified here as type 1 if they induce a FH quantitative deficiency (low FH plasma level) or type 2 if they result in a dysfunctional FH (normal FH plasma level), according to Saunders et al.17 COMPLETE FACTOR H QUANTITATIVE DEFICIENCY (HOMOZYGOUS OR COMPOUND HETEROZYGOUS TYPE 1 MUTATIONS)

The first patient with complete FH deficiency and two episodes of HUS rescued by PE was reported in 1994.18 Subsequently, a large consanguineous Bedouin family was reported. Eleven siblings had aHUS, a homozygous type 1 mutation and complete FH deficiency.19 All had neonatal onset and a relapsing course. The first 10 siblings were treated with PI, daily during acute episodes, weekly between episodes. Eight died of complications of HUS and two went on to ESRD in early life. The sibling reported in 2001 by Landau et al,20 who was initially treated as per his siblings, had a mean of two relapses per month under PI 10 mL/kg weekly, which dropped to one relapse over 9 months when the volume of PI was increased to 15 to 20 mL/kg twice weekly. Serum creatinine was 40 mmol/L at 17 months followup. The effect of plasmatherapy has been reported in a total of five patients with complete FH deficiency3,20–24 (Table 1, patients 12 to 16). Two were treated at the first episode by PI. Spontaneous remission occurred in the three others. Preventive plasmatherapy was instituted in four patients, with PI 10–20 mL/kg from twice weekly to every 2 weeks; one child (patient 16) was treated only during relapses. Plasmatherapy rescued renal function not only in patients with mild renal insufficiency (patients 13,

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674

1–10 wk

10 d

5 mo

8 mo

6 mo

22 d

Ohali et al19

Landau et al20

Nathanson et al21,22

Licht et al23

Sellier-Leclerc et al3

Cho et al24

2–11

12

13

14

15

16

tapered over 3 mo

No. each relapse treated by PI

PI 10 mL/kg weekly  2 yr

PI 20 mL/kg every 2 wk  18 mo

Q1139X, SCR19

/

to weekly after 3 mo

12 d tapered

PI 10 mL/kg 

/

PI 13–15 mL/kg weekly from age 4 to 8 yr

weekly  9 mo (1 relapse)

then 15–20 mL/kg twice

daily during relapses (3.9 relapses/P) PI 10 mL/kg weekly  8 mo (16 relapses),

PI 10 mL/kg weekly between relapses,

independent after 9 mo

No. relapse after 4 mo !50 PE!dialysis-

Long-Term Plasmatherapy

15 mL/kg  3/wk,

106

465

97

/

PI 10 mL/kg daily

PI 10 mL/kg daily

PE (1 L)  21 over 6 wk

Plasmatherapyat First Episode

C1077W,SCR18

Compound HE,

SCR20

HO 3768–71delAGAA

HO Y899X, SCR15

HO Y899X, SCR15

128

274

SCR20

/

SCR20 HO 3749del24bp

1574

Screat mm/L*

HO 3749del24bp

ND, FH < 5%

Genotype

renal function (19 mo)

18 mo, 19 mo. Preserved

Relapses at 2 mo, 9 mo,

(2 yr)

(18 mo) Preserved renal function

Preserved renal function

and ESRD (4 yr)

(PE 60 mL/kg  11 d)

Plasma resistance

(17 mo)

Dialysis: 2 (age 1 yr) Preserved renal function

Death: 8 (age 1–10 mo)

Screat 195 mm/L (6 yr)

Outcome (follow-up)

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*At initiation of plasmatherapy. ND, not documented; PE, plasma exchange; Screat, serum creatinine; to convert from mm/L to mg/mL,  0.0113; HO, homozygous; PI, plasma infusion; P, patient; HE, heterozygous; ESRD, end-stage renal disease. P13 and 15 were reported as P1 and 3, respectively, in Sellier-Leclerc et al.3

19 yr

Pichette et al

1

18

Age at Onset

Author

Patient

Table 1 Plasmatherapy Modalities and Effect in Patients with Complete Factor H Deficiency

PLASMATHERAPY IN ATYPICAL HEMOLYTIC UREMIC SYNDROME/LOIRAT ET AL

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14, and 16) but also in the two with severe renal involvement (patients 12 and 15). Over the long term, all five patients had preserved renal function after 17 months to 4 years on plasmatherapy. By contrast, an untreated child with the same homozygous CFH mutation as patient 15 went on to ESRD within 3 months.25 However, in the child with the longest follow-up (patient 13), a relapse after 4 years on plasmatherapy could not be rescued by daily PE. This secondary plasma resistance was not due to anti-CFH antibodies.22 This patient later presented sudden unilateral blindness after 3 years of dialysis without plasmatherapy, with ischemic/hemorrhagic retinal lesions. Daily PE (60 mL/kg) during 10 days, then three per week, allowed recovery of vision after 4 weeks.26 Landau et al20 were the first to show that 20 mL/kg PI increased FH serum level from near zero to
25% of normal, with a progressive decrease to 10% after 72 hours. This was confirmed by Licht et al,23 who showed that the estimated half-life of FH was
6 days, and that the low C3, AP50, and CH50 levels reflecting complement activation increased after PI and declined progressively thereafter. Thus it appears that in patients with type 1 CFH mutations, who have a quantitative deficiency of FH but no mutant FH in circulation, increasing FH concentration from zero to 25% of normal, and maintaining this level continuously thereafter, may suffice to prevent episodes of HUS. However, the longest published follow-up is only 4 years.22 PARTIAL FACTOR H QUANTITATIVE DEFICIENCY (HETEROZYGOUS TYPE 1 MUTATIONS)

The effect of plasmatherapy is documented in only two patients who probably enter this category because they had FH levels
50% of normal. However no CFH mutation could be identified27,28 (Table 2A, patients 1 and 2). One of them needed 4 months of PE/PI before dialysis withdrawal was possible (patient 1). The other was maintained on weekly plasmatherapy and had moderate renal insufficiency at 3 years follow-up (patient 2). MUTANT DYSFUNCTIONAL FACTOR H (HETEROZYGOUS TYPE 2 MUTATIONS)

Although heterozygous type 2 mutations are the most frequent, the effect of plasmatherapy is documented in only six children16,29–32 (Table 2B, patients 1 to 6). All had mutations in FH SCR 19 or 20, the hot spots for FH binding to C3b and polyanionic sites at cell surface, and five had the same S1191L mutation in SCR20.33 In four patients (patients 2, 3, 4, and 6), the initial episode was rescued by PE, two of them after PI had failed to control the disease. Starting plasmatherapy before renal function is severely impaired probably is important: The four children with a positive response had mild/

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moderate renal failure at treatment initiation (patients 2, 3, 4, and 6; serum creatinine 132 to 166 mmol/L), whereas patient 5, who had PE started 4 weeks after onset, when serum creatinine was 442 mmol/L, did not recover renal function. Subsequently, two children received plasmatherapy only during relapses. Both were in ESRD 4 and 2.5 months after onset, respectively (patients 2 and 5). In contrast, the four patients (patients 1, 3, 4, and 6) who received preventive plasmatherapy, 40 mL/kg FFP infused or exchanged from weekly to every 2 to 3 weeks, all had preserved renal function after 1.5 to 6.5 years under plasmatherapy. However, the child with the longest follow-up developed progressive renal failure after 6.5 years of treatment and reached ESRD within 1 year. The family reported by Davin et al29 suggests that long-term PE therapy may have benefits over PI alone. In these monozygotic twin sisters with S1191L mutation (Table 2B, patients 2 and 3), the first episode of HUS was rescued by PE. Subsequently, the first twin (patient 2) had three relapses within 4 months, each treated by 5 PI, 10 mL/kg. She developed ESRD 4 months after onset. Therefore, the second twin (patient 3) was maintained on a program of prophylactic PE, 40 mL/kg every 2 weeks. After 6 years follow-up, her serum creatinine was 49 mmol/L.29 Of note, all these patients had relapses of HUS despite plasmatherapy, mostly during upper respiratory tract infections, rescued by intensification of treatment at the very first symptom of relapse, generally a slight decrease of platelet count. In conclusion, although published data on plasmatherapy in CFH-HUS is limited, these suggest that (1) early initiation of plasmatherapy is crucial; (2) PE is more effective than PI for remission and prevention of relapses, at least in patients with type 2 CFH mutations; (3) patients maintained on preventive plasmatherapy have a more favorable outcome than patients treated only at the time of relapses; (4) the schedule for longterm preventive plasmatherapy has to be determined empirically for each individual patient, to define the modality (PE or PI), threshold volume, and frequency necessary to maintain remission; (5) too rapid tapering or withdrawal of plasmatherapy generates a risk of relapse and ESRD; (6) plasmatherapy, or at least biological controls, must be intensified during infectious/ inflammatory (e.g., vaccinations) triggers of relapses; (7) it is uncertain whether preserved renal function can be maintained for more than a few years by plasmatherapy. FH concentrate or recombinant FH logically ought to have therapeutic value in patients with type 1 mutations who only need FH repletion. Whether these products will be sufficient in patients with type 2 mutations, for instance during remission for the prevention of relapses, will have to be established.

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676

Author

Gerber et al28

7 mo

4

De et al32

Garrido et al31

Aberrategui-

6 mo

132

HE S1191L, SCR20

HE Y1142C, SCR19

V1197A, SCR20

HE S1191L, SCR20

HE S1191L, SCR20

HE S1191L, SCR20

147

442

166

132

166

HE Insertion of 85 12 amino acids, SCR20

anti-FH antibodies

ND. Low FH, no

1066

over 2 wk

PI !failure then 10 PE

PE/PI during 8 relapses

PI every 2–3 wk  6.5 yr, intensified to daily

PI (3rd episode)

No; 4 episodes over 22 wk, PE (1st 2 episodes),

to twice weekly during 4 relapses

PE started 4 wk after onset

PI 35 mL/kg weekly  18 mo, intensified

PE 40 mL/kg  4 d then twice weekly !remission

PE twice weekly (daily if infection)  1 year then

weekly during 2 relapses

PE 40 mL/kg every 2 wk  6 yr intensified to

No. PI 10 mL/kg  5 during 3 relapses

4–5 wk with PI in between  1.5 yr

PI 30 mL/kg twice weekly or 40–45 mL/kg weekly, or PE 40–45 mL/kg weekly or every

to twice weekly during 4 relapses

20 ml/kg weekly  2 yr 8 mo, intensified

PE weekly from age 7 to 11 mo; then PI

No

Long-Term Plasmatherapy

40 mL/kg  8! failure;

PI 14 mL/kg  3 d; then

PE 40 mL/kg  21 d

PE 40 mL/kg  10 d

No; 4 relapses over 2.5 mo

No; 3 relapses over 4 mo

then PI 15 mL/kg  1 mo

then weekly  3 mo;

PE 40 mL/kg  1 wk;

Screat Plasmatherapy mm/L* at First Episode

ESRD (7.5 yr)

Progressive RI (6.5 yr)

ESRD (2.5 mo)

(2.5 yr)

GFR 102 mL/min/1.73 m2

Screat 62 mm/L (6 yr)

ESRD (4 mo)

Screat 35 mm/L (1.5 yr)

(3 yr)

GFR 50 mL/min/1.73 m2

Screat 212 mm/L (1 yr)

Dialysis- free after 120 d

Outcome (follow-up)

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*At initiation of plasmatherapy. ND, not documented; FH, factor H; Screat, serum creatinine; to convert from mm/L to mg/mL,  0.0113; PE, plasma exchange; HE, heterozygous; GFR, glomerular filtration rate; PI, plasma infusion; ESRD, end-stage renal disease; RI, renal insufficiency.

6

5

et al

30

18 mo

4.5 yr

3 2nd twin Davin et al29

Lapeyraque

4 yr

2 1st twin Davin et al29

1

1 yr

3 mo

Filler et al16

B) FH dysfunction

2

Warwicker27

ND. Low FH

Age at Onset Genotype

A. Partial FH quantitative deficiency 33 yr 1 Stratton and

Patient

Table 2 Plasmatherapy Modalities and Effect in Patients with Partial Factor H Quantitative Deficiency or Dysfunctional Factor H

PLASMATHERAPY IN ATYPICAL HEMOLYTIC UREMIC SYNDROME/LOIRAT ET AL

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PLASMATHERAPY IN PATIENTS WITH MCP OR THBD MUTATION Among aHUS patients, those with MCP mutations and a pediatric onset of the disease have the best prognosis. These patients have a relapsing course but a risk of ESRD of only 15 to 30% at 5 years follow-up.1–4 Adult patients, however, seem to have a more frequent evolution to ESRD within the year after onset. The prognosis of THBD- HUS is poor, with death or ESRD in 60% of patients.1,34 Because MCP and THBD are not circulating proteins, a beneficial effect of plasmatherapy is unlikely to be expected in MCP or THBD-HUS.

Retrospective Series In the Italian registry, of 35 episodes in 14 patients with MCP mutation, 23 were treated (PI 10 to 20 mL/kg and/or PE 30–40 mL/kg, for a total of 2 to 36 treatments in 2 to 6 weeks). Remission (hematologic normalization with or without renal sequel) was observed in 21 of 23 treated episodes and 12 of 12 untreated episodes, confirming that plasmatherapy probably has no benefit in MCP-HUS.2 Also in the French pediatric registry, a favorable outcome was observed in 8 of 9 episodes treated by plasmatherapy (89%) and 15 of 17 untreated episodes (88%).3

Case Reports Treatment modalities and outcome are documented in 24 patients with MCP mutation (pediatric onset in 19, adult onset in 5).35–40 Of 13 patients who received plasmatherapy during all episodes, seven were in ESRD (53%) and 6 had preserved renal function at last follow-up (46%), a proportion similar to that in 11 untreated patients, of whom 5 were in ESRD (45%) and 6 had preserved renal function (55%). However, physicians often choose to perform PE during flares of HUS, to clear up potentially noxious aggregating factors or triggers of endothelial lesions. A recent publication by Davin et al40 illustrates that prophylactic PE probably does not influence the outcome in MCP-HUS. A boy with MCP mutation and HUS at the age of 3 years went into remission after PE. He then received weekly PE for 3.5 years. He had no renal sequelae during 2 years and then developed hypertension, proteinuria, an increase of serum creatinine and LDH, and a decrease of haptoglobin level. Intensification of PE was ineffective, and he was in ESRD 3.5 years after onset. The response to plasmatherapy is not documented in THBD-HUS. Because THBD suppresses not only the complement system but also the coagulation system, its administration as recombinant THBD might be beneficial, as reported in disseminated intravascular coagulation.41

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PLASMATHERAPY IN PATIENTS WITH CFI MUTATIONS Half of CFI-mutated patients go to ESRD within the year after onset, but half recover and have a favorable outcome.1–4,42 Bienaime´ et al recently explained this observation by showing that among 23 patients with CFI mutation, 13 had at least one additional genetic risk factor (a mutation in MCP, CFH, C3, or CFB, or a homozygous deletion of the CFH-related protein [CFHR]1). Ten of these 13 patients presented with ESRD or death within the year after onset. In contrast, none of the patients with isolated CFI mutation had a severe initial outcome.43 Limited information is available about the effect of plasmatherapy in patients with CFI mutation, and it is not always known whether the patients had an isolated or combined CFI mutation.

Retrospective Series Among eight episodes in seven patients with CFI-aHUS from the Italian registry, six were treated by plasmatherapy. Three of the six treated and one of the two untreated episodes had a partial response to plasmatherapy.2

Case Reports The literature gives information for only five patients treated by PE (patient B in Kavanagh et al,44 the three patients in Nilsson et al45) or PI (patient 7 in Fang et al38) at the acute phase. All had complete or partial remission. PE was subsequently maintained in only two patients. All five patients had relapses and all except one (patient 7 in Fang et al38) developed ESRD within a few weeks or months. At least three of these five patients have associated genetic anomalies: patient 2 in Nilsson et al45 had a C3 mutation (patient 16 in Bienaime´ et al43), patient 3 in Nilsson et al45 had a homozygous CFH-R1 deletion and anti-FH antibodies (patient 17 in Bienaime´ et al43), and patient 7 in Fang et al38 had a MCP mutation.

PLASMATHERAPY IN PATIENTS WITH CFB OR C3 MUTATIONS Half of the few patients reported with C346 or CFB47,48 mutations reached ESRD at first episode or within < 1 year after onset. Of four patients with gain-offunction CFB mutation who received PE (patients II7 and III7 of family PER in Goicoechea de Jorge et al47) or PI (patient IV2 in Goicoechea de Jorge et al47 and patient 2 in Roumenina et al48), three were plasma sensitive. Two of them (patient III7 on preventive PE and patient IV2 after cessation of PI) had relapses and were in ESRD after 11 years and within a few months, respectively. The third patient had preserved renal function at 18 months follow-up under monthly PI (patient 2 in Roumenina et al48). The benefit of plasmatherapy in

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PLASMATHERAPY IN ATYPICAL HEMOLYTIC UREMIC SYNDROME/LOIRAT ET AL

Guidelines for Plasmatherapy Recommendations can only be empirical and indicative. Recent guidelines for initial therapy from the European Pediatric Study Group for HUS50 recommend starting plasmatherapy as early as possible, within 24 hours of presentation. This is justified by the frequent rapid deterioration of renal function in patients with CFH, combined CFI, C3, and CFB mutations (and the possibility of anti-CFH antibodies). First-line treatment should be PE, with exchange of 1.5 plasma volume (60 to 75 mL/kg) per session, replaced by FFP. When PE cannot be performed within 24 hours of presentation, PI of 10 to 20 mL/kg should be given if the patient is not volume overloaded and/or hypertensive. PE sessions should be daily for at least 5 days, then five sessions per week for 2 weeks, and then three sessions per week for 2 weeks. Several authors recommend maintaining daily PE until platelet count and LDH level is normalized for several days.51–53 Some patients require daily PE or PI for long periods. Frequency after the first month should be decided according to which risk factor is demonstrated. The demonstration of MCP mutation allows withdrawal of plasmatherapy. For patients with CFH, CFI, C3, CFB mutations, and those with unexplained (no mutation, no anti-FH antibodies) but plasma-sensitive HUS, the possibility to switch from PE to PI, and the maximal interval of time between two sessions need to be determined individually. Plasmatherapy should probably never be stopped in patients with a CFH mutation, and probably also CFI combined mutation, CFB, or C3 mutation. However, an attempt to withdraw plasmatherapy is generally considered in the few patients without any manifestation of HUS despite tapering PE/PI to monthly or less than monthly sessions for several months or years.

THE LIMITS OF LONG-TERM PLASMATHERAPY Practical problems may limit the feasibility of PE over the long term. First, PE requires a technically trained center, especially for young children.54,55 Second, a central venous catheter similar to those used for hemodialysis is necessary if the patient has no arteriovenous fistula. This is associated with the risk of central venous thrombosis, especially in young children, and infection.

Third, some patients develop anaphylactic reactions to FFP, which may require cessation of any form of plasmatherapy. Fourth, as noted earlier, it is uncertain whether the beneficial effect of plasma therapy can persist for decades.

CONCLUSION Today, plasmatherapy remains the first-line treatment in aHUS. However, complement blockers are now available, and several case reports show that one of them, eculizumab, an anti-C5 monoclonal antibody, can replace plasmatherapy in plasma-sensitive patients56,57 and control the disease in plasma-resistant patients.58,59 Prospective trials with eculizumab are presently ongoing. FH concentrate should also be available for therapeutic trials in the years to come, and recombinant FH possibly some day. We hope these new therapeutics will offer patients a better chance of preserved renal function and a better quality of life.

REFERENCES 1. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361(17):1676–1687 2. Caprioli J, Noris M, Brioschi S, et al; International Registry of Recurrent and Familial HUS/TTP. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108(4):1267–1279 3. Sellier-Leclerc AL, Freme´aux-Bacchi V, Dragon-Durey MA, et al; French Society of Pediatric Nephrology. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007;18(8):2392–2400 4. Loirat C, Noris M, Fre´meaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 2008;23(11):1957–1972 5. Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med 1977;297(25): 1386–1389 6. Bukowski RM, King JW, Hewlett JS. Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura. Blood 1977;50(3):413–417 7. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991;325(6):398–403 8. Rock GA, Shumak KH, Buskard NA, et al; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991;325(6):393–397 9. Rizzoni G, Claris-Appiani A, Edefonti A, et al. Plasma infusion for hemolytic-uremic syndrome in children: results of a multicenter controlled trial. J Pediatr 1988;112(2):284–290 10. Loirat C, Sonsino E, Hinglais N, Jais JP, Landais P, Fermanian J; The French Society of Paediatric Nephrology. Treatment of the childhood haemolytic uraemic syndrome with plasma. A multicentre randomized controlled trial. Pediatr Nephrol 1988;2(3):279–285

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patients with a gain of function C3 mutation is documented in only one patient who had complete remission under PE at first episode. A second course of PE to treat a relapse 14 months later induced hematologic remission but did not rescue renal function.49 Maybe very frequent PE is necessary in patients with gain-of-function mutations of CFB and C3, which induce a hyperfunctional C3 convertase.

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11. Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM. Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis 2009;53(2): 259–272 12. Noris M, Remuzzi G. Thrombotic microangiopathy: what not to learn from a meta-analysis. Nat Rev Nephrol 2009; 5(4):186–188 13. Gianviti A, Perna A, Caringella A, et al. Plasma exchange in children with hemolytic-uremic syndrome at risk of poor outcome. Am J Kidney Dis 1993;22(2):264–266 14. Ruggenenti P, Remuzzi G. Pathophysiology and management of thrombotic microangiopathies. J Nephrol 1998;11(6):300– 310 15. Eddy AA, Geary DF, Balfe JW, Clark WF, Baumal R. Prolongation of acute renal failure in two patients with hemolytic-uremic syndrome due to excessive plasma infusion therapy. Pediatr Nephrol 1989;3(4):420–423 16. Filler G, Radhakrishnan S, Strain L, Hill A, Knoll G, Goodship TH. Challenges in the management of infantile factor H associated hemolytic uremic syndrome. Pediatr Nephrol 2004;19(8):908–911 17. Saunders RE, Abarrategui-Garrido C, Fre´meaux-Bacchi V, et al. The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models. Hum Mutat 2007;28(3):222–234 18. Pichette V, Que´rin S, Schu¨rch W, Brun G, Lehner-Netsch G, Delaˆge JM. Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis 1994;24(6): 936–941 19. Ohali M, Shalev H, Schlesinger M, et al. Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H. Pediatr Nephrol 1998;12(8):619–624 20. Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L. Familial hemolytic uremic syndrome associated with complement factor H deficiency. J Pediatr 2001; 138(3):412–417 21. Nathanson S, Fre´meaux-Bacchi V, Descheˆnes G. Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 2001;16(7):554–556 22. Nathanson S, Ulinski T, Fre´meaux-Bacchi V, Descheˆnes G. Secondary failure of plasma therapy in factor H deficiency. Pediatr Nephrol 2006;21(11):1769–1771 23. Licht C, Weyersberg A, Heinen S, et al. Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 2005;45(2):415–421 24. Cho HY, Lee BS, Moon KC, Ha IS, Cheong HI, Choi Y. Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate. Pediatr Nephrol 2007;22(6): 874–880 25. Sethi SK, Marie-Agnes DD, Thaker N, Hari P, Bagga A. Hemolytic uremic syndrome due to homozygous factor H deficiency. Clin Exp Nephrol 2009;13(5):526–530 26. Larakeb A, Leroy S, Fre´meaux-Bacchi V, et al. Ocular involvement in hemolytic uremic syndrome due to factor H deficiency—are there therapeutic consequences? Pediatr Nephrol 2007;22(11):1967–1970 27. Stratton JD, Warwicker P. Successful treatment of factor Hrelated haemolytic uraemic syndrome. Nephrol Dial Transplant 2002;17(4):684–685

2010

28. Gerber A, Kirchhoff-Moradpour AH, Obieglo S, et al. Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality. Pediatr Nephrol 2003;18(9):952–955 29. Davin JC, Strain L, Goodship THJ. Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation. Pediatr Nephrol 2008;23(9): 1517–1521 30. Lapeyraque AL, Wagner E, Phan V, et al. Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations. Pediatr Nephrol 2008; 23(8):1363–1366 31. Abarrategui-Garrido C, Melgosa M, Pen˜a-Carrio´n A, et al. Mutations in proteins of the alternative pathway of complement and the pathogenesis of atypical hemolytic uremic syndrome. Am J Kidney Dis 2008;52(1):171–180 32. De S, Waters AM, Segal AO, Trautmann A, Harvey EA, Licht C. Severe atypical HUS caused by CFH S1191L—case presentation and review of treatment options. Pediatr Nephrol 2010;25(1):97–104 33. Ferreira VP, Herbert AP, Corte´s C, et al. The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. J Immunol 2009;182(11):7009–7018 34. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009;361(4):345–357 35. Richards A, Kemp EJ, Liszewski MK, et al. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A 2003;100(22): 12966–12971 36. Noris M, Brioschi S, Caprioli J, et al; International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 2003; 362(9395):1542–1547 37. Freme´aux-Bacchi V, Moulton EA, Kavanagh D, et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2006;17(7):2017–2025 38. Fang CJ, Fre´meaux-Bacchi V, Liszewski MK, et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 2008;111(2): 624–632 39. Couzi L, Contin-Bordes C, Marliot F, et al. Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair. Am J Kidney Dis 2008;52(2):e5–e9 40. Davin JC, Buter N, Groothoff J, et al. Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome. Pediatr Nephrol 2009;24(9):1757–1760 41. Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007;5(1):31–41 42. Fre´meaux-Bacchi V, Dragon-Durey MA, Blouin J, et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 2004;41(6):e84 43. Bienaime´ F, Dragon-Durey MA, Regnier CH, et al. Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int 2010;77(4):339–349

Downloaded by: University of Wisconsin-Madison. Copyrighted material.

680

44. Kavanagh D, Kemp EJ, Mayland E, et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 2005;16(7): 2150–2155 45. Nilsson SC, Karpman D, Vaziri-Sani F, et al. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol 2007;44(8):1835– 1844 46. Fre´meaux-Bacchi V, Miller EC, Liszewski MK, et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008;112(13): 4948–4952 47. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A 2007;104(1):240–245 48. Roumenina LT, Jablonski M, Hue C, et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 2009;114(13):2837–2845 49. Lhotta K, Janecke AR, Scheiring J, et al. A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure. Clin J Am Soc Nephrol 2009;4(8):1356–1362 50. Ariceta G, Besbas N, Johnson S, et al; European Paediatric Study Group for HUS. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009;24(4):687–696 51. Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001;60(3):831–846

52. Allford SL, Hunt BJ, Rose P, Machin SJ; Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003;120(4):556–573 53. Taylor CM, Machin S, Wigmore SJ, Goodship TH; working party from the Renal Association, the British Committee for Standards in Haematology and the British Transplantation Society. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010;148(1):37–47 54. Michon B, Moghrabi A, Winikoff R, et al. Complications of apheresis in children. Transfusion 2007;47(10):1837–1842 55. Witt V, Stegmayr B, Ptak J, et al. World apheresis registry data from 2003 to 2007, the pediatric and adolescent side of the registry. Transfus Apheresis Sci 2008;39(3):255–260 56. Chatelet V, Fre´meaux-Bacchi V, Lobbedez T, Ficheux M, Hurault de Ligny B. Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant 2009;9(11): 2644–2645 57. Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T. Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis 2010;55(4):708–711 58. Nu¨rnberger J, Philipp T, Witzke O, et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 2009; 360(5):542–544 59. Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 2009;360(5): 544–546

681

Downloaded by: University of Wisconsin-Madison. Copyrighted material.

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